EP0305243B1 - Concentré de protéines coagulables par la thrombine, son procédé d'obtention et son utilisation thérapeutique - Google Patents

Concentré de protéines coagulables par la thrombine, son procédé d'obtention et son utilisation thérapeutique Download PDF

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Publication number
EP0305243B1
EP0305243B1 EP88401961A EP88401961A EP0305243B1 EP 0305243 B1 EP0305243 B1 EP 0305243B1 EP 88401961 A EP88401961 A EP 88401961A EP 88401961 A EP88401961 A EP 88401961A EP 0305243 B1 EP0305243 B1 EP 0305243B1
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EP
European Patent Office
Prior art keywords
protein
fibrinogen
protein concentrate
concentrate
thrombin
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP88401961A
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German (de)
English (en)
French (fr)
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EP0305243A1 (fr
Inventor
Myriana Burnouf
Thierry Burnouf
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Centre Regional de Transfusion Sanguine de Lille
Original Assignee
Centre Regional de Transfusion Sanguine de Lille
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Publication date
Application filed by Centre Regional de Transfusion Sanguine de Lille filed Critical Centre Regional de Transfusion Sanguine de Lille
Priority to AT88401961T priority Critical patent/ATE73341T1/de
Publication of EP0305243A1 publication Critical patent/EP0305243A1/fr
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Publication of EP0305243B1 publication Critical patent/EP0305243B1/fr
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/10—Polypeptides; Proteins
    • A61L24/106—Fibrin; Fibrinogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/36—Blood coagulation or fibrinolysis factors
    • A61K38/363—Fibrinogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics

Definitions

  • the present invention relates to a protein concentrate coagulable by thrombin, its process for obtaining from total plasma and its use for therapeutic purposes.
  • This type of concentrate can be used to obtain an injectable fibrinogen or a biological glue by redissolution.
  • fibrinogen injections can treat states of hypofibrinogemia or constitutional afibrinogenesis, with or without hemorrhages, and also acute defibrination syndromes with severe hemorrhages, in combination with etiological treatment, heparin therapy or anti-fibrinolytics.
  • Biological adhesives make it possible to provide effective help during certain clinical episodes such as skin grafts, nerve or arterial sutures, rapid scarring or any use where a hemostatic and / or bacteriostatic effect and / or aesthetic is sought.
  • fibrinogen a major constituent of such a concentrate, undergoes enzymatic degradation on contact with thrombin activated by calcium ions. After elimination of fibrinopeptides A and B the fibrin monomers then spontaneously polymerize and generate soluble fibrin.
  • the presence of Factor XIII in this type of product helps stabilize fibrin by covalent bonds by making it insoluble, that is to say resistant to solvents, for example urea. The fibrin thus stabilized, in addition to its coagulating role, is more resistant to fibrinolysis and to mechanical traction.
  • Adhesives containing fibrinogen and Factor XIII are already known, in particular from French patents Nos . 2,448,900 and 2,448,901. These products are obtained from plasma cryoprecipitate by treatment with a buffer solution containing an inhibitor-activator of plasminogen or inhibitor of plasmin, which is found present in the glue in the lyophilized state.
  • the known protein concentrates in particular those used as adhesives, do not dissolve in an aqueous medium at room temperature and can even be difficult to dissolve at 37 ° C., forcing the addition of a product to the lyophilization bottle. magnetic bar and to have a magnetic stirrer to accelerate the solution.
  • the concentrate obtained should have a satisfactory content fibrinogen, Factor XIII and fibronectin.
  • the process in question must also easily adapt to modifications aimed at introducing a viral inactivation step.
  • the resulting product should dissolve in less than 10 minutes at the operating temperature (usually 18 to 20 ° C), without the need for special tools.
  • the product should also be stable for several hours to facilitate its use and guarantee its clinical effectiveness.
  • the Applicant has thus developed a simple process which makes it possible to prepare a concentrate of proteins coagulable by thrombin containing, by the simple fact of the fractionation used, more than 70% of coagulable fibrinogen relative to all the proteins present. , and a satisfactory amount of endogenous Factor XIII, by a technique using a plasma fraction available in all fractionation centers.
  • the invention therefore relates to a concentrate of proteins coagulable by thrombin obtained by precipitation and ethanol treatment of human or animal plasma, which advantageously contains more than 70% by weight of coagulable fibrinogen relative to the total proteins and of endogenous Factor XIII. .
  • This concentrate unlike those currently known, dissolves in an aqueous medium at room temperature and this quickly, that is to say in less than 10 minutes for a protein content of up to 150 g / l. Furthermore, it remains stable after reconstitution for at least 24 hours, when it is stored at a temperature of, for example, between 4 and 37 ° C.
  • This concentrate advantageously contains, per gram of protein, at least 100 IU of endogenous Factor XIII.
  • the concentrate is formulated and conditioned so as to obtain after reconstitution by resolubilization a total protein content of the order of 17 to 20 g / l.
  • this content will be between 100 and 120 g / l approximately.
  • the concentrate according to the invention is obtained by a process comprising a step of precipitation with ethanol diluted to a pH close to neutrality and at low temperature, of a total plasma not subjected to cryoprecipitation.
  • the conditions for carrying out the process are adjusted so as to obtain a slightly denatured precipitate, thus avoiding the degradations that the proteins would undergo if the precipitation step were carried out under conventional industrial conditions for plasma processing.
  • the plasma is preferably treated in small containers (for example 10 liters) fitted with magnetic bars.
  • the plasma is therefore brought into contact with ethanol at low concentration, for example 8 to 12%, for a period which can reach several days and in any event greater than 24 hours.
  • the supernatant is then decanted and is available for the preparation of other derivatives.
  • the precipitate obtained after centrifugation is washed with ethanol, always at low temperature, that is to say between 0 and 6 ° C and at an alcoholic degree of 8 to 12%, preferably 10%, and the whole is centrifuged.
  • the precipitate is then redissolved in a Tris / citrate buffer, optionally concentrated, filtered and preferably lyophilized before further treatment.
  • a Tris / citrate buffer optionally concentrated, filtered and preferably lyophilized before further treatment.
  • it can be treated directly, that is to say in the non-lyophilized state.
  • the lyophilisate or the corresponding fresh paste is put back in water solution or Tris / citrate buffer advantageously containing lysine and treating the solution with ethanol diluted hot.
  • the fibrinogen lyophilisate, or the corresponding fresh paste is therefore redissolved at a protein level of the order of 50 g / l and subjected to an ethanol treatment at 8 to 12%, at a temperature between 30 and 40 ° C, preferably at 35 ° C and for a period of the order of an hour and a half.
  • This step preferably carried out in the presence of lysine, contributes to the good re-solution of the lyophilized biological glue, while providing increased security with respect to the inactivation of possible pathogenic viruses, including the AIDS virus. .
  • the amount of lysine used makes it possible, for example, to have a concentration of the order of 0.1 to 0.2 g / gram of protein in the ready-to-use product.
  • the ethanol is removed by ultra-or diafiltration against a buffer preferably containing an amount of lysine corresponding to the desired amount in the ready-to-use product but advantageously free of citrate so that the concentration of this compound in the product final is as low as possible, given its apparently harmful action in coagulation phenomena.
  • a buffer preferably containing an amount of lysine corresponding to the desired amount in the ready-to-use product but advantageously free of citrate so that the concentration of this compound in the product final is as low as possible, given its apparently harmful action in coagulation phenomena.
  • a Tris / NaCl / lysine buffer is used.
  • the product is then sterile filtered, distributed in its use bottle and lyophilized.
  • the lyophilisate, or the corresponding fresh paste, after re-solution is subjected to a viral inactivation step, for example to a treatment with solvent and detergent.
  • a viral inactivation step for example to a treatment with solvent and detergent.
  • the residues from this treatment are then preferably removed by a cold precipitation step with dilute ethanol.
  • the fibrinogen lyophilisate, or the corresponding fresh paste is therefore redissolved at a protein level of the order of 20 g / l. It is then subjected to a viral inactivation treatment, for example to a treatment with a solvent and a detergent according to patent EP-A-0 131 740.
  • This step advantageously carried out at a temperature above 24 ° C and for a duration greater than 6 h, provides increased security with regard to inactivation possible pathogenic viruses, including the AIDS virus and hepatitis viruses. It is preferably used in the presence of lysine from the ready-to-use product of the order of 0.1 to 0.2 g / gram of protein.
  • the elimination of the viral inactivation agents together with the increase in the purity of the protein concentrate is ensured by precipitation of the proteins at low temperature with 8 to 12% ethanol. After centrifugation, viral inactivation agents and contaminating proteins such as albumin are eliminated from the supernatant. If necessary, the precipitate can be brought back into contact with the ethanolic solution in order to ensure better elimination of the viral inactivation agents.
  • the precipitate is redissolved in a Tris-citrate-lysine buffer solution then ultrafiltered and diafiltered, before sterilizing filtration and distribution.
  • Ultrafiltration aims to remove ethanol as well as citrate but allows to maintain a constant lysine content of 0.1 to 0.2 g per gram of protein.
  • the reconstitution of the glue before use is carried out with an aqueous solution of aprotinin at 10,000 UIK / ml, the resulting solution being mixed with calcium thrombin at 500 IU / ml.
  • the product is used either in liquid form dispensed by a double needle system (reconstituted biological glue on the one hand, and calcium thrombin on the other hand) or in dry form (use in powder) or by a vaporization system.
  • the plasma used is obtained by centrifugation of blood and frozen at -35 ° C within 6 hours of collection.
  • For the preparation of the concentrate it is thawed at 37 ° C. It is then subjected to ethanol precipitation. at 10%, pH 7.2, at a protein level of 52 g / l, at a temperature of 4 ° C. The mixture is stirred for 30 minutes then allowed to settle for a minimum of 24 hours at 4 ° C.
  • the ethanolic supernatant is removed by centrifugation and the precipitate, rich in particular in fibrinogen and in Factor XIII, is recovered. This is subjected to a thorough washing using a 10% solution of ethanol pre-cooled to + 4 ° C. and then centrifuged again.
  • the precipitate is then redissolved with a Tris / citrate buffer solution, then concentrated to 15-20 g / l of protein, filtered and optionally lyophilized.
  • the resulting product is resuspended at 50 g / l of protein with a lysine solution corresponding to a lysine content of the final product of 0.1 to 0.2 g / gram of protein, then undergoes a second treatment with 10% ethanol for an hour and a half at 35 ° C.
  • the concentrate is filtered, distributed sterile and lyophilized in the final bottle for re-solution in 0.5 , 1, 2 or 5 ml, for example, during use.
  • the protein composition of the product is as follows (expressed per gram of protein):
  • the plasma used is obtained by centrifugation of blood and frozen at -35 ° C within 6 hours of collection.
  • For the preparation of the concentrate it is thawed at 37 ° C. It is then subjected to precipitation with 10% ethanol, at pH 7.2, at a protein level of 52 g / l, at a temperature of 4 ° C. The mixture is stirred for 30 minutes then allowed to settle for a minimum of 24 hours at 4 ° C.
  • the ethanolic supernatant is removed by centrifugation and the precipitate, rich in particular in fibrinogen and in Factor XIII, is recovered. This is subjected to a thorough washing using a 10% solution of ethanol pre-cooled to + 4 ° C. and then centrifuged again.
  • the precipitate is then redissolved with a Tris / citrate buffer solution, then concentrated to 15-20 g / l of protein, filtered and optionally lyophilized.
  • the resulting product is resuspended at approximately 20 g / l of protein with a lysine solution corresponding to a lysine content of the final product of 0.1 to 0.2 g / gram of protein, then is subjected to a treatment with solvent and detergent containing 0.3% TNBP and 1% Tween® 80 for more than 6 h and at a temperature above 24 ° C.
  • the solution is then subjected to an alcoholic precipitation using 10% ethanol, at 4 ° C., and left to decant for approximately 12 h.
  • the precipitate is recovered and then dissolved in a Tris / citrate buffer containing lysine in an amount corresponding to 0.1-0.2 g of lysine per gram of protein.
  • the concentrate After diafiltration to adjust the ionic strength, remove the citrate and ethanol (but keeping the lysine) and bring the protein content to an adequate value, for example around 35 g / l, the concentrate is filtered, distributed sterile and lyophilized in the final bottle for re-solution in 0.5, 1, 2 or 5 ml, for example, during use.
  • the protein composition of the product is as follows (expressed per gram of protein)
  • the single appended figure represents the results of analysis by electrophoresis on cellulose acetate obtained respectively for this concentrate (curve 1a), and commercial concentrates used as biological adhesives (curves 1b to 1d).
  • the concentrate according to the invention has excellent solubilization and stability characteristics.
  • a biological adhesive As regards a biological adhesive according to the invention, it can be seen that it has excellent characteristics of use for this indication. In fact, its adhesive power is greater than 100 g / cm2 expressed by test on the animal for bonding skin flaps, a value greater than those obtained on other adhesives prepared from cryoprecipitate. This adhesive power is maintained at 90% of its value after reconstitution of the biological glue and storage for 24 hours at 4 ° C or 20 ° C. Furthermore, there is no exudation when mixing the protein concentrate with the thrombin calcium.
  • an adhesive according to the invention derive from its properties; its adhesive and hemostatic power make it a valuable adjunct to surgical procedures during which it saves time operative.
  • its bacteriostatic power strengthens and accelerates the healing of wounds and sutures.
  • an injectable fibrinogen according to the invention, it can be seen that it also has excellent usage characteristics and that its balanced composition makes it a valuable therapeutic agent for the treatment of hypo- or afibrinogenemia states and of acute defibrination syndrome.
  • the usual dose is 1 to 4 g depending on the patient's weight, taking into account that the half-life of fibrinogen is three to four days and the plasma level necessary to have sufficient hemostasis is around 1g / liter.
  • the doses vary from 2 to 10 g depending on the circumstances.
  • the therapeutic products according to the invention can be prepared from human or animal plasma and thus find their interest in both human and veterinary medicine.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Hematology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Diabetes (AREA)
  • Epidemiology (AREA)
  • Immunology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Zoology (AREA)
  • Surgery (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
EP88401961A 1987-07-30 1988-07-28 Concentré de protéines coagulables par la thrombine, son procédé d'obtention et son utilisation thérapeutique Expired - Lifetime EP0305243B1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT88401961T ATE73341T1 (de) 1987-07-30 1988-07-28 Durch thrombine koagulierbares proteinkonzentrat, verfahren zu dessen gewinnung und verwendung als therapeutikum.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR8710798 1987-07-30
FR8710798A FR2618784B1 (fr) 1987-07-30 1987-07-30 Concentre de proteines coagulables par la thrombine, son procede d'obtention et son utilisation a titre de colle biologique

Publications (2)

Publication Number Publication Date
EP0305243A1 EP0305243A1 (fr) 1989-03-01
EP0305243B1 true EP0305243B1 (fr) 1992-03-11

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EP88401961A Expired - Lifetime EP0305243B1 (fr) 1987-07-30 1988-07-28 Concentré de protéines coagulables par la thrombine, son procédé d'obtention et son utilisation thérapeutique

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EP (1) EP0305243B1 (es)
JP (1) JP2787317B2 (es)
AT (1) ATE73341T1 (es)
CA (1) CA1341376C (es)
DE (1) DE3869018D1 (es)
DK (1) DK173568B1 (es)
ES (1) ES2039666T3 (es)
FR (1) FR2618784B1 (es)
GR (1) GR3004047T3 (es)
NO (1) NO174929C (es)

Families Citing this family (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0431072Y2 (es) * 1988-03-14 1992-07-27
FR2639958B1 (fr) * 1988-12-06 1992-08-21 Lille Transfusion Sanguine Support biologique pour cultures cellulaires constitue de proteines plasmatiques coagulees par la thrombine, son utilisation pour la culture des keratinocytes, leur recuperation et leur transport a des fins d'utilisation therapeutique
US6117425A (en) 1990-11-27 2000-09-12 The American National Red Cross Supplemented and unsupplemented tissue sealants, method of their production and use
US7196054B1 (en) 1990-11-27 2007-03-27 The American National Red Cross Methods for treating wound tissue and forming a supplemented fibrin matrix
US6054122A (en) 1990-11-27 2000-04-25 The American National Red Cross Supplemented and unsupplemented tissue sealants, methods of their production and use
US6197325B1 (en) 1990-11-27 2001-03-06 The American National Red Cross Supplemented and unsupplemented tissue sealants, methods of their production and use
DE4202667C1 (es) * 1992-01-29 1993-05-13 Behringwerke Ag, 3550 Marburg, De
AU4693093A (en) * 1992-07-27 1994-02-14 Haemacure Biotech Inc. Biocompatible surgical implant
FR2696095B1 (fr) * 1992-09-30 1994-11-25 Inoteb Colle biologique à base de protéines coagulables par la thrombine, enrichie en facteurs plaquettaires, sa préparation et son application.
US5290918A (en) * 1993-02-23 1994-03-01 Haemacure Biotech Inc. Process for the obtention of a biological adhesive made of concentrated coagulation factors by acidic precipitation
US5395923A (en) * 1993-02-23 1995-03-07 Haemacure-Biotech, Inc. Process for the obtention of a biological adhesive made of concentrated coagulation factors by "salting-out"
US5980866A (en) 1996-03-15 1999-11-09 Juridical Foundation The Chemosero-Therapeutic Research Institute Tissue adhesive suitable for spray application
WO1998055140A1 (en) * 1997-06-05 1998-12-10 Omrix Biopharmaceuticals S.A. Fibrinogen concentrate from human plasma
GB0216001D0 (en) 2002-07-10 2002-08-21 Nat Blood Authority Process and composition
US20060019234A1 (en) * 2004-07-22 2006-01-26 Shanbrom Technologies, Llc Modern blood banking employing improved cell preservation composition
FR2887883B1 (fr) 2005-06-29 2007-08-31 Lab Francais Du Fractionnement Procede de separation des proteines fibrinogene, facteur xiii et colle biologique d'une fraction plasmatique solubilisee et de preparation de concentres lyophilises desdites proteines
FR2894831B1 (fr) 2005-12-16 2008-02-15 Lab Francais Du Fractionnement Colle biologique exempte de thrombine et son utilisation comme medicament.
FR2952641B1 (fr) 2009-11-18 2012-01-13 Lfb Biomedicaments Procede de traitement du plasma sanguin comprenant une etape de lavage par dispersion
FR3032621A1 (fr) 2015-02-13 2016-08-19 Lab Francais Du Fractionnement Colle biologique et son utilisation comme medicament
US20180169297A1 (en) 2015-06-12 2018-06-21 Laboratoire Français Du Fractionnement Et Des Biotechnologies Injectable composition of factor vii and fillers

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4156681A (en) * 1974-03-28 1979-05-29 Plasmesco Ag Process for isolating albumin from blood
AT359652B (de) * 1979-02-15 1980-11-25 Immuno Ag Verfahren zur herstellung eines gewebekleb- stoffes
AT359653B (de) * 1979-02-15 1980-11-25 Immuno Ag Verfahren zur herstellung eines gewebekleb- stoffes
ATE13810T1 (de) * 1981-06-25 1985-07-15 Serapharm Gmbh & Co Kg Angereichertes plasmaderivat zur unterstuetzung von wundverschluss und wundabdeckung.
US4374061A (en) * 1981-07-27 1983-02-15 Center For Blood Research, Inc. Means and methods for purifying Clq, Clr and Cls
DE3203775A1 (de) * 1982-02-04 1983-08-11 Behringwerke Ag, 3550 Marburg Fibrinogenzubereitung, verfahen zu ihrer herstellungund ihre verwendung
DE3228502A1 (de) * 1982-07-30 1984-02-02 Behringwerke Ag, 3550 Marburg Verfahren zur herstellung des c1-inaktivators und seine verwendung
US4540573A (en) * 1983-07-14 1985-09-10 New York Blood Center, Inc. Undenatured virus-free biologically active protein derivatives
AT389815B (de) * 1984-03-09 1990-02-12 Immuno Ag Verfahren zur inaktivierung von vermehrungsfaehigen filtrierbaren krankheitserregern in blutprodukten
US4613501A (en) * 1984-12-21 1986-09-23 New York Blood Center, Inc. Inactivation of viruses in labile blood derivatives

Also Published As

Publication number Publication date
ES2039666T3 (es) 1993-10-01
JPH02114A (ja) 1990-01-05
DK424188D0 (da) 1988-07-29
FR2618784A1 (fr) 1989-02-03
NO174929C (no) 1994-08-03
EP0305243A1 (fr) 1989-03-01
GR3004047T3 (es) 1993-03-31
FR2618784B1 (fr) 1990-04-06
NO883342D0 (no) 1988-07-28
DE3869018D1 (de) 1992-04-16
CA1341376C (fr) 2002-07-16
NO883342L (no) 1989-01-31
JP2787317B2 (ja) 1998-08-13
DK424188A (da) 1989-01-31
ATE73341T1 (de) 1992-03-15
DK173568B1 (da) 2001-03-19
NO174929B (no) 1994-04-25

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